End-stage lung disease from COPD, cystic fibrosis, primary pulmonary hypertension, and ideopathic pulmonary fibrosis affects 15-17 million people in the United States and is the fourth leading cause of death in the U.S. With end-stage lung disease, carbon dioxide retention is a common and grave prognostic sign with limited treatment options. Long-term ventilator management is very restrictive. For emphysema, Lung Volume Reduction Surgery remains investigational as few patients are showing efficacy. Lung transplantation is available to only 900/year as the average wait for a donor is two years with a 30 percent wait-list mortality. An artificial lung is years away. We developed Arteriovenous Carbon Dioxide Removal (AVCO2R) with a low-resistance gas exchanger in a simple percutaneous arteriovenous shunt to achieve near-total extracorporeal removal of CO2 production with only 800-1000 ml/min blood flow. From our animal and patient safety trials, AVCO2 R decreases minute ventilation with an increase in PaO2/FiO2 and no significant change in WBC, platelets, or complement while maintaining CO2 and pH homeostasis. A prototype Ambulatory AVCO2R (A-AVCO2R ) gas exchanger was designed and built by MC3 (Ann Arbor, Mt) for high gas exchange efficiency and very low blood flow resistance. The necessary prototype A-AVCO2R modifications in Phase I were achieved including: 1) optimization and downsizing of the oxygenator design for ambulatory arterio-venous CO2 removal (A-AVCO2R), and 2) implementation of a portable sweep gas control system. For Phase II we will complete the preclinical development of the A-AVCO2R system. Specifically, we will: 1) fabricate the preclinical A-AVCO2R device and vascular attachment cannulae; 2) complete the portable gas flow controller; 3) in vitro performance testing of the entire circuit, then 4a) short-term (1 day) studies to determine gas exchange performance of the entire circuit in normal sheep for final changes; 4b) long-term (1,4, 10 day) studies in ambulatory sheep for preclinical testing of the system and assessment of biocompatibility. Upon completion of this Phase II proposal, we will initiate FDA approval of A-AVCO2R using a simple brachial arteriovenous shunt as a long-term treatment for end-stage lung disease or as a bridge to lung transplantation.